Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of U.S. cancer deaths. Surgical therapy is the only hope as traditional therapy, have failed to improve overall survival. Epithelial-to-mesenchymal transition (EMT) plays a key role in cancer invasion and metastasis. Successful PDAC treatment likely requires therapeutics that attacks multiple pro-tumorigenic pathways in multiple cell types-i.e., treatments that are not yet available. Development of these next-generation agents to treat PDAC is the overall goal of this R21 proposal. We have demonstrated that the putative stem cell protein DCLK1 is overexpressed in various solid tumors and is a central regulator of pluripotency, oncogenic PDAC pathways, and EMT. Inhibition of DCLK1 leads to activation of endogenous tumor-suppressors in the tumor, which in turn regulate oncogenes involved in cancer growth, pluripotency maintenance, and EMT. Targeting cells that overexpress DCLK1 blocks tumor growth in animal models. The goal for this proposal is to assess the feasibility of using small molecule inhibitor (XMD8- 92) that block DCLK1 kinase activity as a new therapeutic approach to improve PDAC treatment outcomes. We will pursue three Specific Aims: (1) Determine an effective dose of XMD8-92. (2) Determine an effective dose of XMD8-92 that will suppress primary and metastatic tumor formation. (3) Determine the molecular mechanism by which XMD8-92 regulates key oncogenic downstream pathways in PDAC cells. Overall, upon completion of this study, we should be able to demonstrate a minimal effective dose of XMD8-92 against PDAC using various tumor models. Development of an small molecule kinase inhibitor directed at critical targets such as DCLK1 could lead more effective treatment and potential cure of PDAC and improve overall survival.